Tumors at hypoxic regions cause invasive, metastatic and chemoresistant cancers, and are the biggest factor preventing a complete cure of cancer. There is an urgent desire for the development of methods for treating tumor cells in such low-oxygen environments.
Several kinds of clinical trials are currently being conducted on the following and other drugs targeted at cancer cells in hypoxic regions: triapazamine, AQ4N (banoxantrone dihydrochloride), PR104 (dinitrobenzamide nitrogen mustard prodrug) and TH-302 (N,N′-bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl) methyl ester. However, at present, there is no information to indicate that these have been brought to market.
Dinitrobenzamide and other compounds which act as such protecting groups are disclosed in Non-Patent Document 1 and nitroimidazoles relating to TH-302 are disclosed in Non-Patent Document 2, Patent Document 1 and Patent Document 2. TH-302, as shown in the following reaction scheme, is understood to utilize the mechanism of cleaving the protecting group-drug bond to release the drug.

In both Patent Documents 1 and 2, the drug is bonded through a methyleneoxy group (—CH2—O—) to a carbon atom on the imidazole ring, and is understood to be released from the prodrug by the same mechanism as in the above reaction scheme. However, in this system, the efficiency of drug release is dependent on the leaving ability of the drug; the drug that is released is limited to a compound having a phenolic hydroxyl group or phosphoric acid that readily dissociates.
Patent Document 3 mentions a hypoxia-activated conjugate (Hyp-L-Q) obtained by covalently bonding a bioreductive group (Hyp: e.g., 2-nitroimidazolyl) at the 1 position thereon through a linker (L: —CH2CH2CH2—C═O)—) to the amino group on an anthracycline-based anticancer agent (Q). With regard to this compound which is a conjugate, in a hypoxic tumor region, although the -L-Q moiety remained bonded, the nitro group on 2-nitroimidazolyl is reduced to hydroxyamine, which suggests that DNA can be alkylated through the 4- or 5-position on imidazolyl and that, at the same time, the anthracycline making up Q is intercalated between DNA bases, thereby killing cancer cells. However, it was revealed in this patent publication that a compound in which the linker is “—C3H6-C(═O)—”, as compared with a corresponding compound in which the linker is —CH2(CH2)aCH2—O—CH2— (“a” here being the integer 0 or 1), for example, exhibits only a very low cytotoxicity to lung cancer cells under hypoxic conditions. Hence, such a compound falls outside the scope of the claims of this patent application.
In addition, Patent Document 4 mentions that amides such as N-methyl-2-nitro-1-imidazole propanoylamide, for example, have a radiation-sensitizing action and also have, by themselves, an anticancer effect. However, no mention or suggestion whatsoever has been made that such imidazole carboxylic acids can be used to form conjugates or prodrugs with other drugs.